2H-Pyran, tetrahydro-3-(phenylmethyl)-

Endpoint summary

Description of key information

Skin irritation: not irritating (OECD 404, GLP, K, Rel.1)

Eye irritation: irritating (OECD 405, GLP, K, Rel.1)

Key value for chemical safety assessment

Skin irritation / corrosion

Link to relevant study records

Reference

Endpoint:

skin irritation: in vivo

Type of information:

experimental study

Adequacy of study:

key study

Study period:

14 to 21 December, 2004

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Remarks:

GLP study conducted according to OECD Guideline 404 with deviations: age at study initiation, feeding conditions not reported. These deviations do not affect the quality of the study and are not considered to be relevant. The substance is considered to be adequately characterised.

Qualifier:

according to guideline

Guideline:

OECD Guideline 404 (Acute Dermal Irritation / Corrosion)

Version / remarks:

24 April 2002.

Deviations:

yes

Remarks:

age at study initiation, feeding conditions not reported

Qualifier:

according to guideline

Guideline:

EU Method B.4 (Acute Toxicity: Dermal Irritation / Corrosion)

Version / remarks:

Directive n° 2004/73/EC.

Deviations:

yes

Remarks:

age at study initiation, feeding conditions not reported

Principles of method if other than guideline:

Not applicable

GLP compliance:

yes (incl. QA statement)

Remarks:

Inspected 2004-07-01 / Signed 2004-09-13

Species:

rabbit

Strain:

New Zealand White

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Elevage de Gérome, Quartier Labaste – F40260 Linxe - FRANCE
- Weight at study initiation: 2.24-2.60 kg
- Housing: Each animal was kept in an individual box installed in conventional air conditioned animal husbanding.
- Diet: No data
- Water: No data
- Acclimation period: at least 5 days

ENVIRONMENTAL CONDITIONS
- Temperature: 19-21 °C
- Humidity: 28-54 %

IN-LIFE DATES: 14 to 21 December, 2004

Type of coverage:

semiocclusive

Preparation of test site:

not specified

Vehicle:

unchanged (no vehicle)

Remarks:

undamaged skin area

Controls:

other: On the left flank an untreated area was served as the control

Amount / concentration applied:

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 0.5 mL
- Concentration (if solution): Undiluted

Duration of treatment / exposure:

4 h

Observation period:

1 hour and then 24, 48, 72 hours and Days 4 after removal of the patch.

Number of animals:

3 males

Details on study design:

TEST SITE
- Area of exposure: The test item was applied, as supplied, at a dose of 0.5 mL, on an undamaged skin area of the right flank of each animal.
- Type of wrap if used: The patch was secured in position with a strip of surgical adhesive tape.

REMOVAL OF TEST SUBSTANCE
- Time after start of exposure: 4 h

OBSERVATION TIME POINTS
- Skin reactions were appreciated 1 hour and then 24, 48, 72 hours and Days 4 after removal of the patch.

SCORING SYSTEM: According to OECD guideline 404

Irritation parameter:

erythema score

Basis:

animal #1

Remarks:

mean individual score

Time point:

24/48/72 h

Score:

1

Max. score:

4

Reversibility:

fully reversible within: 4 days

Remarks on result:

probability of weak irritation

Irritation parameter:

edema score

Basis:

animal #1

Remarks:

mean individual score

Time point:

24/48/72 h

Score:

0

Max. score:

4

Reversibility:

other: not applicable

Remarks on result:

no indication of irritation

Irritation parameter:

erythema score

Basis:

animal #2

Remarks:

mean individual score

Time point:

24/48/72 h

Score:

1

Max. score:

4

Reversibility:

fully reversible within: 72 hours

Remarks on result:

probability of weak irritation

Irritation parameter:

edema score

Basis:

animal #2

Remarks:

mean individual score

Time point:

24/48/72 h

Score:

0

Max. score:

4

Reversibility:

other: not applicable

Remarks on result:

no indication of irritation

Irritation parameter:

erythema score

Basis:

animal #3

Remarks:

mean individual score

Time point:

24/48/72 h

Score:

0.3

Max. score:

4

Reversibility:

fully reversible within: 48 hours

Remarks on result:

probability of weak irritation

Irritation parameter:

edema score

Basis:

animal #3

Remarks:

mean individual score

Time point:

24/48/72 h

Score:

0

Max. score:

4

Reversibility:

other: not applicable

Remarks on result:

no indication of irritation

Irritant / corrosive response data:

Twenty four hours after the test product application, it was noted, on the treated area, a slight to moderate erythema. These erythematous reactions were totally reversible between the 3rd and the 5th day of the test.
On the cutaneous structure, it was noted a dryness between the 3rd and 6th day of the test in one animal, between the 4th and the 6th day in a second one and between the 4th and the 7th day in the last one. The skin recovered a normal aspect between the 7th and the 8th day of the test.

Other effects:

None

Table 7.3.1/1: Individual and average scores after 4 h exposure

Observations		Scores
Skin reactions	Observation time	Animal No. A6365	Animal No. A6371	Animal No. A6372
Erythema	1h	0	1	1
	24h	1	2	1
	48h	1	1	0
	72h	1	0	0
	Day 4	0	-	-
	Mean 24/48/72h	1	1	0.3
Oedema	1h	0	0	0
	24h	0	0	0
	48h	0	0	0
	72h	0	0	0
	Day 4	0	0	0
	Mean 24/48/72h	0	0	0

Interpretation of results:

GHS criteria not met

Conclusions:

Under the test conditions, test substance is not classified as irritating to skin according to the criteria of the Regulation EC No. 1272/2008 (CLP) and to the GHS.

Executive summary:

In a dermal irritation study performed according to the OECD Guideline No. 404, and in compliance with GLP, undiluted test substance was applied at the dose of 0.5 mL, under semiocclusive dressing during 4 hours on an undamaged skin area of 3 rabbits. On the opposite flank an untreated area was served as the control. Skin irritation was assessed and scored according to the Draize scale at 1, 24, 48, 72 h and Day 4 after the removal of the patch.

 

Twenty four hours after the test product application, it was noted, on the treated area, a slight to moderate erythema. These erythematous reactions were totally reversible between the 3rd and the 5th day of the test.

On the cutaneous structure, it was noted a dryness between the 3rd and 6th day of the test in one animal, between the 4th and the 6th day in a second one and between the 4th and the 7th day in the last one. The skin recovered a normal aspect between the 7th and the 8th day of the test.

The individual scores for each animal within 3 scoring times (24, 48 and 72 h) were 1.0 / 1.0 / 0.3 for erythema and 0.0 / 0.0 / 0.0 for oedema. 

 

Under the test conditions, the test substance is not classified according to the criteria of the Regulation EC No. 1272/2008 (CLP) and to the GHS.

This study is considered as acceptable and satisfies the requirement for skin irritation endpoint.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed (not irritating)

Eye irritation

Link to relevant study records

Reference

Endpoint:

eye irritation: in vivo

Type of information:

experimental study

Adequacy of study:

key study

Study period:

20 December 2004 to 03 January 2005

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Remarks:

GLP study conducted according to OECD Guideline 405 with deviations: age at study initiation, feeding conditions not reported. These deviations do not affect the quality of the study and are not considered to be relevant. The substance is considered to be adequately characterised.

Qualifier:

according to guideline

Guideline:

OECD Guideline 405 (Acute Eye Irritation / Corrosion)

Version / remarks:

24 April 2002

Deviations:

yes

Remarks:

age at study initiation, feeding conditions not reported

Qualifier:

according to guideline

Guideline:

EU Method B.5 (Acute Toxicity: Eye Irritation / Corrosion)

Version / remarks:

Directive n° 2004/73/EC.

Deviations:

yes

Remarks:

age at study initiation, feeding conditions not reported

Principles of method if other than guideline:

Not applicable

GLP compliance:

yes (incl. QA statement)

Remarks:

Inspected 2004-07-01 / Signed 2004-09-13

Species:

rabbit

Strain:

New Zealand White

Details on test animals or tissues and environmental conditions:

TEST ANIMALS
- Source: Elevage de Gérome, Quartier Labaste – F40260 Linxe - FRANCE
- Weight at study initiation: 2.34-2.75 kg
- Housing: Each animal was kept in an individual box installed in conventional air conditioned animal husbanding.
- Diet: No data
- Water: No data
- Acclimation period: at least 5 days

ENVIRONMENTAL CONDITIONS
- Temperature: 20-21 °C
- Humidity: 30-52 %

IN-LIFE DATES: 20 December 2004 to 03 January 2005

Vehicle:

unchanged (no vehicle)

Controls:

other: untreated eye serving as control

Amount / concentration applied:

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 0.1 mL
- Concentration (if solution): Undiluted

Duration of treatment / exposure:

No washing was done

Observation period (in vivo):

Ocular examinations were performed on both right and left eyes 1, 24, 48, 72 h and Day 4 to Day 11 following treatment, according to a numerical evaluation.

Number of animals or in vitro replicates:

3 males

Details on study design:

TREATMENT
A volume of 0.1 mL of the pure test item was instilled into the conjunctival sac of one eye, the other eye remained untreated serving as control. Initially, a single animal was treated. After consideration of the ocular responses produced in the first treated animal, two additional animals were treated.

REMOVAL OF TEST SUBSTANCE
- Washing: No

SCORING SYSTEM: According to OECD guideline 405

Irritation parameter:

cornea opacity score

Basis:

animal #1

Remarks:

mean individual score

Time point:

24/48/72 h

Score:

2

Max. score:

4

Reversibility:

fully reversible within: Day 11

Remarks on result:

positive indication of irritation

Irritation parameter:

iris score

Basis:

animal #1

Remarks:

mean individual score

Time point:

24/48/72 h

Score:

0.3

Max. score:

2

Reversibility:

fully reversible within: Day 7

Remarks on result:

probability of weak irritation

Irritation parameter:

conjunctivae score

Basis:

animal #1

Remarks:

mean individual score

Time point:

24/48/72 h

Score:

1.3

Max. score:

3

Reversibility:

fully reversible within: Day 8

Remarks on result:

probability of weak irritation

Irritation parameter:

chemosis score

Basis:

animal #1

Remarks:

mean individual score

Time point:

24/48/72 h

Score:

1

Max. score:

4

Reversibility:

fully reversible within: Day 7

Remarks on result:

probability of weak irritation

Irritation parameter:

cornea opacity score

Basis:

animal #2

Remarks:

mean individual score

Time point:

24/48/72 h

Score:

1.7

Max. score:

4

Reversibility:

fully reversible within: Day 4

Remarks on result:

probability of mild irritation

Irritation parameter:

iris score

Basis:

animal #2

Remarks:

mean individual score

Time point:

24/48/72 h

Score:

0.3

Max. score:

2

Reversibility:

fully reversible within: 48 h

Remarks on result:

probability of weak irritation

Irritation parameter:

conjunctivae score

Basis:

animal #2

Remarks:

mean individual score

Time point:

24/48/72 h

Score:

2

Max. score:

3

Reversibility:

fully reversible within: Day 6

Remarks on result:

probability of mild irritation

Irritation parameter:

chemosis score

Basis:

animal #2

Remarks:

mean individual score

Time point:

24/48/72 h

Score:

1.3

Max. score:

4

Reversibility:

fully reversible within: Day 5

Remarks on result:

probability of weak irritation

Irritation parameter:

cornea opacity score

Basis:

animal #3

Remarks:

mean individual score

Time point:

24/48/72 h

Score:

1.3

Max. score:

4

Reversibility:

fully reversible within: Day 4

Remarks on result:

probability of mild irritation

Irritation parameter:

iris score

Basis:

animal #3

Remarks:

mean individual score

Time point:

24/48/72 h

Score:

0

Max. score:

2

Reversibility:

other: not applicable

Remarks on result:

no indication of irritation

Irritation parameter:

conjunctivae score

Basis:

animal #3

Remarks:

mean individual score

Time point:

24/48/72 h

Score:

1.3

Max. score:

3

Reversibility:

fully reversible within: Day 7

Remarks on result:

probability of weak irritation

Irritation parameter:

chemosis score

Basis:

animal #3

Remarks:

mean individual score

Time point:

24/48/72 h

Score:

0.3

Max. score:

4

Reversibility:

fully reversible within: 48 h

Remarks on result:

probability of weak irritation

Irritant / corrosive response data:

The ocular reactions observed during the study have been slight to moderate, and totally reversible in the three animals:
- at the conjunctivae level: a moderate enanthema, noted 24 hours after the test product instillation and totally reversible between the 7th and the 9th day of the test, associated with a slight to moderate chemosis, noted 24 hours after the test product instillation and totally reversible between the 3rd and the 8th day of the test ;
- at the corneal level: a moderate opacity, registered 24 hours after the test product instillation, and totally reversible between the 5th and the 12th day of the test,
- at the iris level: a congestion, registered 24 hours after the test product instillation in 2 animals, and between the 5th and the 7th day of the test in one animal

Other effects:

None

Table 7.3.2/1: Individual and mean scores of conjunctivae, iris and cornea

Time / Animal	Cornea			Iris			Conjunctivae
							redness			chemosis
	1 (A6389)	2 (A6394)	3 (A6395)	1 (A6389)	2 (A6394)	3 (A6395)	1 (A6389)	2 (A6394)	3 (A695)	1 (A6389)	2 (A6394)	3 (A6395)
1 h	0	0	0	0	0	0	1	2	1	1	1	1
24 h	2	2	2	1	1	0	2	2	2	1	2	1
48 h	2	2	1	0	0	0	1	2	1	1	1	0
72 h	2	1	1	0	0	0	1	2	1	1	1	0
D4	2	0	0	1	0	0	1	1	1	1	1	0
D5	2	0	0	1	0	0	1	1	1	1	0	0
D6	2	0	0	1	0	0	1	0	1	1	0	0
D7	1	-	0	0	-	0	1	-	0	0	-	0
D8	1	-	-	0	-	-	0	-	-	0	-	-
D9	1	-	-	0	-	-	0	-	-	0	-	-
D10	1	-	-	0	-	-	0	-	-	0	-	-
D11	0	-	-	0	-	-	0	-	-	0	-	-
Mean 24/48/72 h	2.0	1.7	1.3	0.3	0.3	0.0	1.3	2.0	1.3	1.0	1.3	0.3

Interpretation of results:

Category 2A (irritating to eyes) based on GHS criteria

Conclusions:

Under the test conditions, the test substance is classified in Category 2 (H319: Causes serious eye irritation) according to the criteria of the Regulation EC No. 1272/2008 (CLP) and classified in Category 2A (irritating to eyes) according to the GHS.

Executive summary:

In an eye irritation study conducted according to OECD 405 Guideline and in compliance with GLP, test substance was instilled as supplied, into the eye of 3 New Zealand rabbits at the dose of 0.1 mL, the other eye remained untreated serving as control. The lids were then gently held together for about one second in order to prevent loss of the test substance. The eyes were examined and the changes were observed at 1, 24, 48 and 72 h and 4 to 11 days after treatment and graded according to the Draize method.  

 

The ocular reactions observed during the study have been slight to moderate, and totally reversible in the three animals:

- at the conjunctivae level: a moderate enanthema, noted 24 hours after the test product instillation and totally reversible between the 7th and the 9th day of the test, associated with a slight to moderate chemosis, noted 24 hours after the test product instillation and totally reversible between the 3rd and the 8th day of the test ;

- at the corneal level: a moderate opacity, registered 24 hours after the test product instillation, and totally reversible between the 5th and the 12th day of the test,

- at the iris level: a congestion, registered 24 hours after the test product instillation in 2 animals, and between the 5th and the 7th day of the test in one animal.

 

Mean individual scores at 24, 48 and 72 h after exposure for the 3 animals were 2.0, 1.7, 1.3 for cornea score; 0.3, 0.3, 0.0 for iris score; 1.3, 2.0, 1.3 for conjunctivae score and 1.0, 1.3, 0.3 for chemosis score.

 

Under the test conditions, the test substance is classified in Category 2 (H319: Causes serious eye irritation) according to the criteria of the Regulation EC No. 1272/2008 (CLP) and classified in Category 2A (irritating to eyes) according to the GHS.

This study is considered as acceptable and satisfies the requirement for eye irritation endpoint.

Endpoint conclusion

Endpoint conclusion:

adverse effect observed (irritating)

Respiratory irritation

Endpoint conclusion

Endpoint conclusion:

no study available

Additional information

Skin irritation:

A key study was identified (Phycher, 2005). In this dermal irritation study performed according to the OECD Guideline No. 404, and in compliance with GLP, 3 male New Zealand White rabbits were exposed for 4 hours to a semi-occluded application of 0.5 mL of undiluted test material to the intact skin. Initially, a single animal was treated. After consideration of the cutaneous responses produced in the first treated animal, two additional animals were treated.

The individual scores for each animal within 3 scoring times (24, 48 and 72 h) were 1.0 / 1.0 / 0.3 for erythema and 0.0 / 0.0 / 0.0 for oedema. The substance is therefore not classified for skin irritation.

 

Eye irritation:

A key study was identified (Phycher, 2005). In this eye irritation study performed according to the OECD guideline 405, and in compliance with GLP, 0.1 mL of undiluted test material was instilled into one eye of 3 female New Zealand White rabbits. The other eye remained untreated and served as control. The lids were then gently held together for about one second in order to prevent loss of the test substance. The eyes were examined and the changes were observed at 1, 24, 48 and 72 h and 4 to 11 days after treatment and graded according to the Draize method.

Mean individual scores at 24, 48 and 72 h after exposure for the 3 animals were 2.0, 1.7, 1.3 for cornea score; 0.3, 0.3, 0.0 for iris score; 1.3, 2.0, 1.3 for conjunctivae score and 1.0, 1.3, 0.3 for chemosis score.

The effects observed were all reversible within 11 days. The substance is therefore classified as eye irritating.

Justification for classification or non-classification

Harmonized classification:

The substance has no harmonized classification according to the Regulation (EC) No. 1272/2008 (CLP).

Self classification:

Based on the available data:

- no additional self-classification is proposed regarding skin irritation according to the CLP and to the GHS.

- the substance is classified in Category 2 (H319: Causes serious eye irritation) according to the CLP and classified in Category 2A (irritating to eyes) according to the GHS.

- No data was available regarding respiratory irritation.